Connections between epigenetic gene silencing and human disease

https://doi.org/10.1016/j.mrfmmm.2006.05.038Get rights and content

Abstract

Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene expression is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease.

Section snippets

DNA methylation

Altered gene expression can play a causal role in human disease. In many cases, altered expression results from genetic lesions within the gene or regulatory sequences. However, in some cases genetic lesions are absent from the locus. In such instances, aberrant epigenetic modifications of the chromatin surrounding the gene are the cause of altered expression. There are two major epigenetic gene silencing mechanisms that account for a growing number of diseases: cytosine DNA methylation and

Histone methylation

Modifications such as phosphorylation, acetylation and methylation frequently occur on histones tails that extend from the nucleosome core [20]. These modifications serve to alter charge interactions of the histone tails with DNA, thereby influencing chromatin packaging. In addition, these modifications serve as binding sites for specific factors that “read” a proposed histone code [21]. In most cases, specific modifications correlate with biological functions such as chromatin condensation,

HP1 and disease

One function of K9H3 methylation is to serve as a binding site for HP1 (Fig. 1b). HP1 is conserved among species, with mice and humans each possessing three genes encoding HP1-like proteins [61]. In humans these are referred to as HP1Hsα, HP1Hsβ and HP1Hsγ. These proteins share significant amino acid sequence identity, yet have distinct chromosomal localization patterns [61], [62], [63]. HP1 proteins contain a chromo domain that binds methylated K9H3, and a chromo shadow domain that dimerizes

Connections among epigenetic gene silencing systems

Through the course of investigating the role of epigenetic modifications involved in disease, connections among DNA methylation, histone acetylation and histone methylation have become apparent (Fig. 1). Studies in model organisms have revealed a connection between DNA methylation and histone methylation. In Neurospora, a screen for mutants that lacked CpG DNA methylation identified a K9H3 histone methyltransferase [93]. In Arabidopsis, mutants lacking a histone H3 methyltransferase show

Dynamics of epigenetic modifications and therapy

The dynamic nature of epigenetic gene regulation is important to consider in the context of disease. Both the loss and gain of gene silencing at target genes can potentially be reversed through drug treatment [106]. Drugs that inhibit DNA methylation can reactivate silenced genes in cancer cells, possibly re-establishing cell cycle control [107]. Drugs that inhibit histone deacetylation block cell cycle progression and cause apoptosis by unknown mechanisms [107]. While HDAC inhibitors alter the

Acknowledgements

We apologize to the many investigators whose research could not be cited due to space limitations. We would like to thank Al Klingelhutz and members of the Wallrath Lab for comments on the manuscript, and Judith Kassis for discussions. Research is supported by an NIH grant (GM61513) to L.L.W., a grant from the Department of Defense Breast Cancer Research Foundation (DAMD17-02-1-0424) to L.L.W. and a Susan G. Komen Dissertation Research Award (DISS0403121) to T.J.M.

References (144)

  • F.M. Raaphorst et al.

    Poorly differentiated breast carcinoma is associated with increased expression of the human polycomb group EZH2 gene

    Neoplasia

    (2003)
  • D.F. Dukers et al.

    Unique polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin's lymphoma-derived cell lines

    Am. J. Pathol.

    (2004)
  • A.H. Peters et al.

    Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability

    Cell

    (2001)
  • S. Czvitkovich et al.

    Over-expression of the SUV39H1 histone methyltransferase induces altered proliferation and differentiation in transgenic mice

    Mech. Dev.

    (2001)
  • A.L. Nielsen et al.

    Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins

    Mol. Cell

    (2001)
  • N.P. Cowieson et al.

    Dimerisation of a chromo shadow domain and distinctions from the chromodomain as revealed by structural analysis

    Curr. Biol.

    (2000)
  • L. Fanti et al.

    The heterochromatin protein 1 prevents telomere fusions in Drosophila

    Mol. Cell

    (1998)
  • K. Song et al.

    Human Ku70 interacts with heterochromatin protein 1alpha

    J. Biol. Chem.

    (2001)
  • L.E. Norwood et al.

    A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion

    J. Biol. Chem.

    (2006)
  • P.S. Steeg et al.

    Metastasis suppressor genes: basic biology and potential clinical use

    Clin. Breast Cancer

    (2003)
  • C. Lim et al.

    Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus functionally interacts with heterochromatin protein 1

    J. Biol. Chem.

    (2003)
  • L. Johnson et al.

    Interplay between two epigenetic marks. DNA methylation and histone H3 lysine 9 methylation

    Curr. Biol.

    (2002)
  • B. Lehnertz et al.

    Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin

    Curr. Biol.

    (2003)
  • M. Ehrlich et al.

    DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes

    Hum. Mol. Genet.

    (2001)
  • P.A. Wade

    Methyl CpG-binding proteins and transcriptional repression

    Bioessays

    (2001)
  • A.H. Lund et al.

    Epigenetics and cancer

    Genes Dev.

    (2004)
  • C. Boltze et al.

    Silencing of the maspin gene by promoter hypermethylation in thyroid cancer

    Int. J. Mol. Med.

    (2003)
  • B.W. Futscher et al.

    Aberrant methylation of the maspin promoter is an early event in human breast cancer

    Neoplasia

    (2004)
  • Y. Yatabe et al.

    Maspin expression in normal lung and non-small-cell lung cancers: cellular property-associated expression under the control of promoter DNA methylation

    Oncogene

    (2004)
  • K. Delaval et al.

    Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

    Bioessays

    (2006)
  • A. Lewis et al.

    How imprinting centres work

    Cytogenet. Genome Res.

    (2006)
  • D. Biniszkiewicz et al.

    Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality

    Mol. Cell Biol.

    (2002)
  • A.C. Bell et al.

    Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene

    Nature

    (2000)
  • N. Schonherr et al.

    (Epi)mutations in 11p15 significantly contribute to Silver–Russell syndrome: but are they generally involved in growth retardation?

    Eur. J. Med. Genet.

    (2006)
  • A.H. Hassan et al.

    Promoter targeting of chromatin-modifying complexes

    Front Biosci.

    (2001)
  • W.A. Bickmore et al.

    Perturbations of chromatin structure in human genetic disease: recent advances

    Hum. Mol. Genet.

    (2003)
  • E. Li

    Chromatin modification and epigenetic reprogramming in mammalian development

    Nat. Rev. Genet.

    (2002)
  • M. Tudor et al.

    Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • J.I. Young et al.

    Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • B.D. Strahl et al.

    The language of covalent histone modifications

    Nature

    (2000)
  • M.F. Fraga et al.

    Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

    Nat. Genet.

    (2005)
  • A. Kuzmichev et al.

    Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein

    Genes Dev.

    (2002)
  • J. van der Vlag et al.

    Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation

    Nat. Genet.

    (1999)
  • E. Vire et al.

    The Polycomb group protein EZH2 directly controls DNA methylation

    Nature

    (2006)
  • P. Taghavi et al.

    Developmental biology: two paths to silence merge

    Nature

    (2006)
  • I.H. Su et al.

    Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement

    Nat. Immunol.

    (2003)
  • D. O’Carroll et al.

    The polycomb-group gene Ezh2 is required for early mouse development

    Mol. Cell Biol.

    (2001)
  • A.P. Bracken et al.

    Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions

    Genes Dev.

    (2006)
  • X. Tang et al.

    Activated p53 suppresses the histone methyltransferase EZH2 gene

    Oncogene

    (2004)
  • T. Tonini et al.

    Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A

    Oncogene

    (2004)
  • Cited by (0)

    View full text